ABSTRACT Hepatitis C Virus (HCV) infection, the most common chronic blood-borne viral infection in the US, disproportionately affects homeless and drug-using populations, creating a significant health disparity and representing a critical focus for effective prevention at the individual and community level. Compared to the general population, homeless persons have a 26-fold increase in HCV prevalence, a diagnosis strongly associated with injection drug use (IDU). Focused screening, early detection and treatment for homeless adults are critical for effective treatment. Yet while interferon-based HCV treatment protocols have shown efficacy in 60% of patients, many do not continue treatment as a result of severe side- effects. Further, only 1-6% of illicit drug-using HCV-infected persons receive any treatment, despite current treatment guidelines. Successful treatment for HCV with direct acting antiviral (DAA) drug regimens may provide an alternative solution, targeting specific steps along the HCV lifecycle. These treatments have not been assessed among homeless adults. Factors associated with low adherence to hepatitis treatment among homeless adults include untreated mental illness, ongoing drug and alcohol use, unstable housing, and limited access to care. To address these disparities, we will pilot test a theoretically-based innovative model of care, successfully implemented by our team in other vulnerable populations, among HCV-infected homeless persons. Utilizing a community-based delivery approach, a community health worker (CHW), guided by a registered nurse (RN), will deliver a CHW/RN program, with HCV medication treatment delivered using directly observed therapy (DOT) to eligible HCV-infected homeless adults. For the first time, using a community-based approach, our CHW/RN team will implement the intervention program which includes administration of DAA in the community where the participant lives, rather than a health care facility. In Phase I, using community participatory approaches, we plan to develop and refine the culturally-sensitive intervention program, focusing on reducing health disparities. Acceptability and feasibility will be rigorously evaluated. In Phase 2, we will assess the impact of the CHW/RN intervention among 108 eligible HCV-infected homeless adults in Los Angeles, primarily on HCV treatment completion, and cure, and secondarily on mental health, substance use, access to care and shelter stability, as compared with a primary care clinic-based standard of care (cbSOC) model. Individual-level factors that are potential mechanisms that underlie health disparities in completing HCV treatment (e.g., social support, stable housing, mental illness) will be evaluated. We hypothesize that our CHW/RN-based model will be superior to the cbSOC program at improving HCV treatment completion, preventing progression of HCV disease, and improving secondary outcomes (e.g., mental health, access to care, etc). By extension, our intervention, if effective, could help reduce transmission of HCV infection among at-risk homeless persons and could help ameliorate certain health disparities. We plan for findings to inform a larger trial in a future R01 NIH application. This engagement in treatment as prevention is urgent since this HCV-infected group represents a reservoir for HCV infection in the general population.